Bis-nitrogen heterocyclic compounds and a method of their preparation



V 3,164,599 Patented Jan. 5, 1965 3,164,599 I BIS-NITROGEN HETEROCYCLICCOMPOUNDS AND A METHOD OF THEIR PREPARATKON Henry Rapoport, Berkeley,Calif., assignor to California Research Corporation, San Francisco,Calif., a corporation of Delaware No Drawing. Filed Nov. 28, 1960, Ser.No. 71,88 4 Claims. (Cl. 260-288) This invention relates to a processfor preparing bisnitrogen heterocyclic compounds from pyridine,quinoline, pyrrole, and related materials. In particular, the process ofthe invention pertains to the reaction of nitrogen heterocycliccompounds in the presence of a palladium catalyst to form thecorresponding bis-nitrogen heterocyclic compounds.

Bis-nitrogen heterocyclic compounds of the invention are of particularinterest in the chemical industry as a result of their unique propertiesas complexing agents for copper and other metallic ions. Theirsensitivity permits detection of copper in concentrations as low as onepart in one-hundred million. Certain of the compounds are also valuablechemical intermediates.

Heretofore, the yields obtained from methods of the prior art for thepreparationof these bis-nitrogen heterocycles, such as 2,2-biquinolyls,have been quite poor. For example, one method of preparation of2,2'-biquinolyl by the condensation of an o-aminobcnzaldehyde or ano-aminophenone with a Z-acylquinoline requires the laborious preparationof intermediates and still provides only very poor yields. Other methodshave been used, but they too require the preparation of intermediatesand give extremely poor yields. In the preparation of 2,2-biquinolyl bymethods of the prior art, a yield of 5 percent is considered high. 7

It has now been discovered that various bis-nitrogen heterocycliccompounds such as 2,2'-biquinolyl,' 2,2-bipyridyl, or 2,2-bipyrrole maybe simply and effectively prepared by heating quinoline, pyridine, orpyrrole, respectively, at reflux temperature, i.e., between about 110 to400 C., in the presence of a. palladium catalyst. In cases however,where the reflux temperature is above that at which products orreactants tend to decompose, an inert diluent may be used to lower thereflux temperature of the system below the decomposition temperature. Onthe other hand, moreover, if the reflux temperature of the startingmaterial is too low to provide a reasonable reaction rate, ahigh-boiling diluent or super-atmospheric pressure may be used tosufficiently increase the temperature of reflux and, accordingly, thereaction rate. A conversion of 2,2'-biquinolyl of as high as 17 percentper pass in comparison With 5 percent by the better methods of the priorart may be obtained by the process of the invention. Still anotheradvantage ofthe invention is the fact that a major proportion of thestarting materials which are not converted to the bis-nitrogenheterocyclic compounds remains unaflected by the catalyst and hence maybe recovered and recycled so as to obtain an over-all yield of thedesired bis-nitrogen heterocycle based on starting material consumed ofas high as 70 to 90 percent.

The heterocyclic nitrogen starting materials for the process of theinvention can be certain quinolines, naphthyridines, pyridines,pyrroles, and similar heterocycles.

, In addition, Z-mthylquinoline may be converted to 1,2

di-Z-quinolylethane by the process of the invention. These materials maybe unsubstituted or may have lower alkyl, lower alkoxy, of phenylsubstituents onany avail able ring positions above three. For example,the compound quinoline, having the following structural formula isitself a suitable material for the process of the invention, or it mayhave substituents in the 4, 5, 6, 7, or '8 positions.

From starting materials of the invention which are unsubstituted in. the2 position, the bis-compound is formed by a direct linkage at the 2position. For example, quinoline forms 2,2'-biquinolyl, represented:

In the case of Z-methylquinolines, the bis-nitrogen heterocycliccompounds formed therefrom are joined by their Z-methyl groups.Z-methylquinoline forms the compound l,2-di-2-quinolylethane,structurally represented as follows:

The process of the invention, in more detail, is as follows. Theheterocyclic nitrogen starting material is heated under reflux in thepresence of a palladium catalyst. The amount of catalyst used and theprecise type are not critical. From '5 to 20 percent of a supportedcatalyst by weight of reaction mixture has been found suitable, aboutlOpercent being preferred. The catalyst may be any conventional supportedpalladium hydrogenation catalyst; For example, commercially available 5or tetrachloride, or benzene, to remove all adsorbed material therefrom.These washing solutions are combined with the reaction mixture so thatsolvent may be removed from.

the entire mixture in one operation by an extractive distillation. Wherethe starting material is sufliciently volatile to permit its separationfrom the product by distillation,"

the starting material may be recovered overhead, leaving product asbottoms. In those instances where the starting material is notsufficiently volatile to be separated from the product by distillation,it may be separated by sublimation or by chromatography on an aluminacolumn.

The reaction may be carriedout under atmospheric conditions or, ifdesired, may be carried out in the absence of oxygen, such as under a Catmosphere.

The advantages'and details of the invention can perhaps be betterunderstood by a reference to the following ex- EXAMPLE 1 Quinoline wasstirred and heated under reflux at about 238 C; in the presence of 10percent by Weight of a 5 I percent palladium-on-carbon catalyst forabout 24 hours. The mixture was then cooled, parts by volume chloroformwere added, and the resulting mixture heated to boiling and filtered.Any product or unreacted starting material adsorbed on the catalyst wasremoved by subsequent digestions of the catalyst with chloroform. Thischloroform solution was admixed with the original solution containingthe product and the remainder of the unreacted starting material. Thecombined chloroform solution was first distilled to remove chloroformand then further distilledto recover the unreacted starting material.

The residue from the distillation was purified by chromatography on analumina column. A'solid was obtained which melted at 196 C. This was a17-percent conversion of quinoline to 2,2'-biquinolyl. Unreactedquinoline was recovered, showing an 85-percent yield based uponquinoline consumed.

EXAMPLE 2 Pyridine was stirred and heated under reflux at about 115 C.in the presence of 10 percent by weight of a 5 percentpalladium-on-carbon catalyst for about 24 hours. The mixture was thencooled, '10 parts by volume chloroform were added, and the resultingmixture heated to boiling and filtered. Any product or unreactedstarting material adsorbed on the catalyst was removed by subsequentdigestions of the catalyst with chloroform. This chloroform solution wasadmixed with the original solution containing the product and theremainder of the unreacted starting material. The combined chloroformsolution was first distilled to remove chloroform and then furtherdistilled to recover the unreacted starting material.

The residue from the distillation was purified by chromatography on analumina column. A solid was obtained which melted at 70 to 71 C. and wasanalyzed to be EXAMPLE 3 chloroform. This chloroform solution wasadmixed with i the original solution containing the product and theremainder of the unreacted starting material. The combined chloroformsolution was first distilled to remove chloroform and then furtherdistilled to recover the unreacted starting material.

. The residue from the distillation was purified by chromatography on analumina colunm. A solid was obtained which melted at 210 to 211 C. andwas analyzed to be 8,8-dimethyl-2,2-biqu'inolyl.

EXAMPLE 4 I 7 '4-phenylquinoline was stirred and heated at about 360 C.in the presence of 10 percent by weight of a 5 percentpalladium-on-carbon catalyst for about 24 hours. The mixture was thencooled, 10 parts by volume chloroform were added, and the resultingmixture heated to boiling and filtered. Any product or-unreactedstarting material adsorbed on the catalyst was removed by subsequentdigestions of the catalyst with chloroform. This chloroform solution wasadmixed with the original solution containing the product and theremainder of the unreacted starting material. The combined chloroformsolution was first distilled to remove chloroform and then furtherdistilled to recover the unreacted starting material.

The residue from the distillation was purified by chromatography on analumina column. A solid was obtained which melted at 358 to 360 C. andthen analyzed to be 4,4'-diphenyl-2,2'-biquinolyl.

EXAMPLE 5 Pyrrole was stirred and heated at about 131 C. in the presenceof 10 percent by weight of a5 percent palladiumon-carbon catalyst forabout 24 hours. I The mixture was then cooled, 10 parts by volumechloroform were added, and the resulting mixture heated toboiling andfiltered. Any product or unreacted starting material adsorbed on thecatalyst was removed by subsequent digestions of the catalyst withchloroform. This'chloroform solution was fi-methoxyquinoline was stirredand heated at about 265 C. in the presence of 10 percent by weight of a5 percent palladi'um-on-carbon catalyst for about 24 hours. The mixturewas then cooled, 10 parts by volume chloroform were added, and theresulting mixture heated to boiling and filtered. Any product orunreacted starting material adsorbed on the catalyst was removed bysubsequent digestions of the catalyst with chloroform. This chloroformsolution was admixed with the original solution containing the productand the remainder of the unreacted starting material. The combinedchloroform solution was first distilled to remove chloroform and thenfurther distilled to recover the unreacted starting material.

The residue from the distillation was purified by treatment bychromatography on an alumina column. A solid was obtained which meltedat 280 to 281 C. and was analyzed to be 6,6'-dimethoxy-2,2'-biquinolyl.

Analysis Element I Theory I Found EXAMPLE 7 1 volume chloroform wereadded, and the resulting mixture I heated to'boiling and filtered. Anyproduct or unreacted starting material adsorbed on the catalyst wasremoved by subsequent digestions of the catalyst with chloroform. Thischloroform solution was admixed with the original solution containingtheproduct and the remainder of the unreacted starting material. Thecombined chloroform solution was first distilled to remove chloroformand then flllitl'lel distilled to recover the unreacted starting matetheoriginal solution containing the product and the re- The residue fromthe distillation was purified by chm; matography on an alumina column. Asolid was obtained which melted at 282 to 284 C. and was analyzed to be2,2'-bi-l,5-naphthyridyl.

4,6-dimethylpyridine was stirred and heated under reflux at about 157 C.in the presence of percent by weight of a 5 percent palladium-on-carboncatalyst. for about 24 hours. The mixture was then cooled, 10 parts byvolume chloroform were added, and the resulting mixture heated toboiling and filtered. Any product or unreacted starting materialadsorbed on the catalyst was removed by subsequent digestions of thecatalyst with chloroform. This chloroform solution was admixed withm'ainder of the unreacted starting material. The com- 25 binedchloroform solution was first distilled to remove chloroform and thenfurther distilled to recover the unreacted starting material. v Theresidue from the distillation was purified by chromatography on analumina column. A solid was obtained which melted at 144 to 145 C. andwas analyzed to be 4,4,6,6-tetramethyl-2,2-bipyridyl.

Analysis Element Theory Found C 79.3 79.3 H 7.5 7.5 N 13.2 13.2

EXAMPLE 9 the remainder of the unreaoted star-ting material. Thecombined chloroform solution was first distilled to remove chloroformand then further distilled to remove the unreaoted starting material.

The residue from the distillation was purified by chromatography on analumina column. A solid was obtained which melted at 166 to 167 C. andwas 1,2-di-2-quinolylethane.

As will be evident to those skilled in the art, various modifications onthis process can be made or followed, in the light of the foregoingdisclosure and discussion, without departing from the spirit or scope ofthe disclosure or from the scope of the claims.

I claim:

1. A process for preparing bis-nitrogen heterocyclic compounds selectedfrom the class consisting of 2,2'-biquinolyl, 2,2-\binaphthyridyl, 2,2bipyridyl, 1,2 di 2- quinolylethane, 2,2'-bipyrnole, and substitutedmembers thereof which comprises heating at reflux temperature in thepresence of a palladium hydrogenation catalyst a compound possessing aboiling point between about 400 C. selected from the class consisting ofquinoline, naphthyridine, pyridine, Z-methylquinoline, pyrrole, andsubstituted members thereof, said substitutents being located on ringpositions above 3 and being selected from the class consisting of loweralkyl, lower alkoxy, and phenyl.

2. A process according to claim 1, wherein the catalyst ispelladium-on-carbon.

3. A process for preparing 2,2'-biquinoly-l which comprises heatingquinoline at reflux in the presence of a palladium hydrogenationcatalyst.

4. 2,2-bi-l,5-naphthyridyl.

References Cited in the file of this patent UNITED STATES PATENTSHammick et al: J. Chem. Soc., pp. 2436-41 (1955).

Badger et al.: J. Chem. Soc., pp.. 616-620 (1956). Linnell: J. OrganicChem., vol. 22, pp. 1691-92 Nakano: Pharmaceutical Society of Japan(Journal), vol. 79, pp. 310-319 (1959).

Rapoport et al.: J. Organic Chem, vol. 25, pp. 372 373 (1960 analyzed tobe

1. A PROCESS FOR PREPARING BIS-NITROGEN HETERCOCYCLIC COMPOUNDS SELECTEDFROM THE CLASS CONSISTING OF 2,2''-BIQUINOLYL, 2,2''-BINAPHTHYRIDYL,2,2'' - BIPYRIDYL, 1,2 -DI - 2QUINOLYLETHANE, 2,2''-BIPYRROLE, ANDSUBSTITUTED MEMBERS THEREOF WHICH COMPRISES HEATING AT REFLUXTEMPERATURES IN THE PRESENCE OF A PALLADIUM HYDROGENATION CATALYST ACOMPOUND POSSESSING A BOILING POINT BETWEEN ABOUT 110* 400*C. SELECTEDFROM THE CLASS CONSISTING OF QUINOLINE, NAPTHYRIDINE, PYRIDINE,2-METHYLQUIOLINE, PYRROLE, AND SUBSTITUTED MEMBERS THEREOF, SAIDSUBSTITUTENTS BEING LOCATED ON RING POSITIONS ABOVE 3 AND BEING SELECTEDFROM THE CLASS CONSISTING OF LOWER ALKYL, LOWER ALKOXYL, AND PHENYL.